Causative agents of Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis): A meta-analysis

Objective: Kikuchi-Fujimoto disease (KFD) is a self-limiting disorder characterized by histiocytic necrotizing lymphadenitis in the cervical lymph nodes of young women. Although an infectious etiology has been postulated, a definitive causative agent has not been identified. The few dozens of published studies are limited by small sample size and poorly structured study designs. The purpose of this study is to evaluate the association of each infectious agent to KFD that has been studied. Methods: We performed metaanalysis using major electronic database (MEDLINE (PubMed), Cochrane library, Embase, Web of Science, NML gateway, LILACS, and Google Scholar). Cross-sectional studies on the positivity of each agent in clinicopathologically diagnosed KFD and normal controls by polymerase chain reaction (PCR) or in situ hybridization (ISH) were carefully retrieved. The included infectious agents were herpes simplex virus (HSV) type 1, 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus (EBV), human herpes virus (HHV) 6, 7, 8, parvovirus B19, human papilloma virus, hepatitis B virus, human T-lymphotropic virus 1, Brucella, and Bartonella henselae. Results: After an exclusion process of 2491 studies, five, two, four, two, two, and three studies on EBV-PCR, EBV-ISH, HHV6-PCR, HHV8-PCR, parvovirus B19-PCR and HHV7-PCR, respectively, were suitable for quantitative meta-analysis. Conclusion: The most suspected pathogen, EBV was not associated to KFD than normal controls (odds ratio. = 0.28, p= 0.005), while the HHV8 positivity was more likely to be associated (odds ratio. = 8.24, p= 0.003) although it still needs further verification. None of other viruses was associated to KFD although the results are limited by small sample size. More studies with large sample size and strict sample selection criteria are necessary in future.